Selective angiotensin-converting enzyme C-domain inhibition is sufficient to prevent angiotensin I-induced vasoconstriction

Department of Pharmacology, Erasmus MC, Rotterdam, The Netherlands.
Hypertension (Impact Factor: 7.63). 01/2005; 45(1):120-5. DOI: 10.1161/01.HYP.0000151323.93372.f5
Source: PubMed

ABSTRACT Somatic angiotensin-converting enzyme (ACE) contains 2 domains (C-domain and N-domain) capable of hydrolyzing angiotensin I (Ang I) and bradykinin. Here we investigated the effect of the selective C-domain and N-domain inhibitors RXPA380 and RXP407 on Ang I-induced vasoconstriction of porcine femoral arteries (PFAs) and bradykinin-induced vasodilation of preconstricted porcine coronary microarteries (PCMAs). Ang I concentration-dependently constricted PFAs. RXPA380, at concentrations >1 mumol/L, shifted the Ang I concentration-response curve (CRC) 10-fold to the right. This was comparable to the maximal shift observed with the ACE inhibitors (ACEi) quinaprilat and captopril. RXP407 did not affect Ang I at concentrations < or =0.1 mmol/L. Bradykinin concentration-dependently relaxed PCMAs. RXPA380 (10 micromol/L) and RXP407 (0.1 mmol/L) potentiated bradykinin, both inducing a leftward shift of the bradykinin CRC that equaled approximately 50% of the maximal shift observed with quinaprilat. Ang I added to blood plasma disappeared with a half life (t(1/2)) of 42+/-3 minutes. Quinaprilat increased the t(1/2) approximately 4-fold, indicating that 71+/-6% of Ang I metabolism was attributable to ACE. RXPA380 (10 micromol/L) and RXP407 (0.1 mmol/L) increased the t(1/2) approximately 2-fold, thereby suggesting that both domains contribute to conversion in plasma. In conclusion, tissue Ang I-II conversion depends exclusively on the ACE C-domain, whereas both domains contribute to conversion by soluble ACE and to bradykinin degradation at tissue sites. Because tissue ACE (and not plasma ACE) determines the hypertensive effects of Ang I, these data not only explain why N-domain inhibition does not affect Ang I-induced vasoconstriction in vivo but also why ACEi exert blood pressure-independent effects at low (C-domain-blocking) doses.

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Available from: Joep van Esch, Sep 01, 2015
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    • "Despite the structural identity of the two domains, there are some variations between the active sites, that results in a specific affinity for substrates and designing precise inhibitors. Lack of adequate C-domain specificity for ACE inhibitors, leads to bradykinin accumulation (Van Esch et al., 2005), which result in several adverse side effects associated, such as dry cough and angioedema (Morimoto et al., 2004). On the other hand, in hypotensive patients nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation is induced by Ang II that ends up in oxidative stress, an important factor in cardiovascular diseases and hypertension. "
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    • "Porcine meningeal artery segments clearly responded to the endogenous ligands noradrenaline, 5-HT, as well as CGRP and to phenylephrine, demonstrating that at least α-adrenoceptors, 5-HT 2A and CGRP 1 receptors are functionally active. In addition, studies from our laboratory using pig hearts obtained from the same slaughter house have shown that coronary artery segments responded to a number of compounds, including angiotensin, angiotensin-converting enzyme inhibitors, bradykinin, and nitric oxide donors (Tom et al. 2002; Batenburg et al. 2004; Van Esch et al. 2005; Gupta et al. 2006a). Similarly, we have ensured that not only noradrenaline and phenylephrine, but also sumatriptan, ergotamine, dihydroergotamine, BHT-933 and UK-14304 did indeed contract another blood vessel, namely the human isolated saphenous vein (see Fig. 5). "
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